The rockefeller university

The loss and mutation of Topoisomerase 3 beta (TOP3B), the only known eukaryotic topoisomerase with the ability to catalyze RNA strand passage reactions, is linked to schizophrenia, autism, and intellectual disability. Uniquely, TOP3B primarily localizes to the cytoplasm and has been shown to regulate translation and stability of a subset of mRNA transcripts. Three neurological disease-linked de novo TOP3B point mutations outside of the active site have been identified but their impact on TOP3B activity in cells remains poorly understood. Upon establishing a new Neuro2A cell-based TOP3B activity assay, we provide genetic and biochemical evidence that the autism-linked C666R mutation causes accumulation of unresolved TOP3B center dot mRNA covalent intermediates by directly disrupting metal coordination via an atypical D1C3-type metal binding motif within the zinc finger domain. Furthermore, we show that primary neurons are sensitive to TOP3B center dot mRNA covalent intermediates, including those formed by the C666R mutant TOP3B, and that such adducts are capable of causing ribosome collisions. Together, these data identify a previously underappreciated role of the zinc finger domain and how non-active site disease-linked mutations affect TOP3B activity and neuronal toxicity.

Myeloid cells-including monocytes, macrophages, dendritic cells, and granulocytes-are critical architects of the tumor microenvironment, in which they exert diverse functions ranging from immunosuppressive to immunostimulatory. Advances in single-cell omics and high-dimensional immune profiling have unveiled the remarkable heterogeneity and plasticity of these cells, revealing lineage-specialized functions that shape cancer immunity. These discoveries have sparked growing interest in therapeutically targeting myeloid cells as a next-generation strategy in cancer immunotherapy. As a complementary or alternative approach to T cell-centered immunotherapies, myeloid-directed therapies offer unique opportunities to reprogram the immune landscape, enhance antitumor responses, and overcome resistance mechanisms. In this review, we highlight recent discoveries in myeloid cell biology in cancer and discuss emerging therapeutic targets, with an emphasis on antibody-based therapies that have reached clinical development. We further provide perspective on translational challenges to implement these approaches into the clinic and discuss how Fc-engineering and rational antibody design can optimize myeloid cell engagement and amplify their immune effector functions. Together, these advances position myeloid-directed immunotherapies as a promising approach to enhance the efficacy and durability of cancer treatment.

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is a common complication following transjugular intrahepatic portosystemic shunt (TIPS) insertion. However, the prognostic significance of overt HE post-TIPS remains controversial. METHODS: We screened 2137 patients who underwent TIPS insertion at 8 German tertiary care centers between 2004 and 2021. Patients with pre-emptive TIPS placement, hepatocellular carcinoma, missing data, and non-PTFE covered stents were excluded. Competing risk analysis was performed, considering liver transplantation as a competing event. To correct for immortal time bias, landmark analyses were conducted, with the landmark being set at 30 and 90 days post-TIPS. Outcome data were assessed for up to 30 months post-TIPS insertion. RESULTS: A total of 1356 patients (median Model for End-stage Liver Disease [MELD], 13 [interquartile range (IQR), 10-17]; age, 60 years [IQR, 54-67 years]; 64% male; 12% HE before TIPS), were included. Overall, HE post-TIPS was linked to impaired survival (P < .001; subdistribution hazard ratio [sHR], 1.41; 95% confidence interval [CI],1.15-1.73). However, this was only confirmed if HE occurred within the first 30 days post-TIPS (early HE; P < .001; sHR, 2.02; 95% CI, 1.59-2.57). Additionally, patients with a history of HE (P < .001; sHR, 1.59; 95% CI, 1.21-2.07) and history of HE and early HE post-TIPS (P < .001; sHR, 3.44; 95% CI, 2.34-5.04) showed impaired survival. These findings were confirmed in the landmark and multivariable analyses. CONCLUSIONS: Early HE post-TIPS is associated with significantly reduced survival. Therefore, patients who experience early HE or have a history of HE should be closely monitored by physicians, as they constitute a particularly vulnerable group with impaired survival.

BackgroundHybrid effectiveness-implementation designs evaluate the effectiveness and implementation of interventions. We retrospectively evaluated the implementation of a stepped-wedge cluster randomized controlled trial of a facilitated telemedicine model (experimental) integrated into opioid treatment programs (OTPs) compared to offsite referral (control) for hepatitis C virus (HCV) treatment. The trial period was March 2017-October 2022. We compared organizational and implementation characteristics associated with an HCV cure and with high satisfaction with healthcare delivery.MethodsWe used the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework to guide data collection and evaluation. We evaluated the clinical effectiveness outcome (HCV cure) and patient-centered outcomes (changes between in-person and telemedicine patient satisfaction questionnaire subscales: Time Spent With Doctor and General Satisfaction). We evaluated 7 organizational and 16 implementation variables. We used random forests to obtain a list of variables with total importance weight of at least 95%. We subsequently conducted a configurational comparative method of coincidence analysis (CNA) to identify the variable combinations that are associated with the best outcomes.ResultsThe effectiveness of reach was enhanced by site identification of HCV RNA positive individuals. We found that low patient load per provider or counselor, site liaison presence, and high case manager availability increased clinical effectiveness (i.e., HCV cure). Adoption and implementation, assessed by high healthcare delivery satisfaction among participants in both arms, was associated with site liaisons, frequent case manager onsite presence and consistency, and low provider patient volume. Among telemedicine participants, onsite notifications and provider involvement in recruitment were additional variables associated with high healthcare satisfaction. In referral, providing patient education, low counselor patient volume, case manager involvement in site activities, and high case manager education levels were additional variables associated with high healthcare delivery satisfaction. Intervention maintenance has occurred at 10 sites.ConclusionsCompared to referral, facilitated telemedicine requires fewer variables for high effectiveness and patient satisfaction. The frequent onsite presence and consistency of the case manager and low provider and counselor volumes improved outcomes among both approaches. Improved outcomes among referral participants required more publicity, patient education, higher case manager education, more involvement in site activities, and occurred in university-affiliated sites.Trial registrationClintrials.gov registration number NCT02933970; Comparison of Telemedicine to Usual Care for HCV Management for Methadone-maintained Individuals Full Text View ClinicalTrials.gov.

Zika virus (ZIKV) is an emerging arbovirus, and its infection is often asymptomatic or mild; however, it can lead to severe neurological disorders. Currently, there are no approved treatments or vaccines for ZIKV, highlighting the urgent need to explore potential therapeutic options. In this study, we evaluated the antiviral activity of a novel synthetic peptide (GA-peptide) against ZIKV in vitro. The GA-peptide exhibited dose-dependent inhibition of the virus, affecting multiple stages of the ZIKV replication cycle. It demonstrated virucidal activity and effectively protected Vero cells from ZIKV infection. Additionally, the GA-peptide disrupted viral entry by targeting both the attachment and internalization phases, as well as post-entry stages of the infection. In silico analyses identified potential viral targets that interact with the GA-peptide. These findings underscore the GApeptide's promising potential as a therapeutic agent against ZIKV and its relevance in the development of new antiviral drugs.

Over the past decade, radio frequency (RF) sensing or radar has garnered great interest as an emerging modality to enable human-computer interaction via gesture recognition. Current approaches involve utilization of a radar system that transmits a fixed signal with predetermined frequency, bandwidth, and other waveform parameters. However, gesture recognition accuracy can be greatly impacted by radar transmission parameters, which affect computational load and performance. In this work, we introduce a human-centered, fully adaptive radar (HC-FAR) system for ambient gesture recognition in which a programmable, software-defined radar system dynamically changes its RF transmission in response to human behavior. We design and switch between different transmission modes for different human-computer interaction tasks-human presence detection, trigger detection, and command translation-as well as alter processing so as to minimize computational load. In this way, the proposed HC-FAR paradigm enables dynamic management of the tradeoffs between dimensionality of RF data representations and their resulting computational load with real-time classification accuracy. Our results show that HC-FAR significantly reduces the allocation of computational and spectral resources, while enhancing fine-grain gesture recognition via a joint domain multi-input deep neural network, which takes as input the RF micro-Doppler signature, range, and angle profile.

Mosaic loss of the Y chromosome (mLOY) is the most common somatic event in men, strongly associated with aging and various health conditions. Current methods for detecting mLOY primarily rely on DNA genotyping arrays. Here, we present MosCoverY, a method for estimating mLOY from exome or whole-genome sequencing data. MosCoverY addresses the challenges posed by the structure of the Y chromosome by focusing on single-copy genes and normalizing their coverage against autosomal exons matched by length and GC content. We validated it using data from 212,062 male participants in the UK Biobank, comparing the results to those obtained using genotyping-or whole-genome-sequencing-based methods. MosCoverY identified mLOY in 5.6% of men, demonstrating performance that was comparable to the other methods. We validated our approach by replicating known mLOY associations with age, smoking, all-cause mortality, and germline genetic loci. We further confirmed the robustness of our method at lower sequencing depth and demonstrated its applicability in single-sample analysis. Finally, we used data from The Cancer Genome Atlas to demonstrate that MosCoverY can also reliably detect variable mLOY in tumoral genomes. MosCoverY offers a valuable tool for detecting mLOY from exome or genome data in population-scale studies.

T helper cell subsets-Th1, Th2, and Th17-coordinate pathogen-specific immune responses. Candida albicans-specific T cells include protective Th17 cells alongside other Th subsets. However, the role of alternative Th subsets remains unclear, particularly in individuals with impaired Th17 responses and recurrent candidiasis. Here, we show that patients with STAT1 gain-of-function mutations and chronic mucocutaneous candidiasis have a numerically normal but functionally altered pool of C. albicans-specific Th cells, skewed toward Th1 and Th2. This imbalance persisted even when assessing responses to the known and the newly identified immunodominant C. albicans antigens MP65 (65-kilodalton mannoprotein), HYR1 (hyphally regulated cell wall protein 1), and SAP4-6 (secreted aspartic proteinases 4-6), suggesting that antigen recognition and priming remain intact despite qualitative defects in T cell polarization. Using mucosal infection mouse models, we demonstrate that C. albicans-specific transgenic Th17 cells are sufficient to control infection, whereas Th1 and Th2 cells fail to protect, even in high numbers. Moreover, co-transfer of Th2 cells with Th17 cells impaired fungal control via an IL-4-dependent mechanism. These findings highlight the essential role of Th17 cells in protective immunity against C. albicans and reveal that non-Th17 responses are ineffective and may contribute to susceptibility in both humans and mice.

Background: Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being approved by the US Food and Drug Administration. Although vitiligo is primarily regarded as a TH1/interferon-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear. Objective: We sought to obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo. Methods: We performed bulk RNA sequencing combined with real-time PCR and immunohistochemistry of skin biopsy samples from 15 lesional and nonlesional vitiligo samples and compared them to 14 matched healthy controls. Results were corroborated by single-cell RNA sequencing. Results: Robust inflammatory dysregulation was captured not only in lesional but also nonlesional vitiligo skin relative to healthy controls. Lesional samples demonstrated upregulation of TH1 (OASL, CXCL9, CXCL10), TH2 (IL4, IL4R, CCL13, CCL17, CCL22, CCL26), and TH17/22 (IL20, S100A7, S100A8, S100A9, PI3) related markers. Similarly, nonlesional samples demonstrated activation of TH1 (CXCL9, OASL), TH2 (IL4R, IL10, CCL13, CCL17, CCL22), and TH17/22 (PI3, DEFB4A) associated markers. Clinical severity scores (Vitiligo Area Scoring Index and/or Vitiligo Disease Activity Index) significantly and positively correlated with multiple inflammatory mediators (ie, CXCL14, IL25, IL17RC) in lesional and/or nonlesional vitiligo skin. On a single-cell level, IL13 and IFNG expression were primarily found in nonlesional helper T cells and in lesional proliferating T cells, respectively. Conclusions: Our findings show that immune dysregulation in vitiligo involves immune axes beyond TH1/Tc1, with particular upregulation of type 2 markers already observed in nonlesional skin, suggesting a role during early lesion formation. (J Allergy Clin Immunol 2025;156:993-1007.)